Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/06—Dipeptides
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
  • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
  • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/05—Dipeptides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/10—Antimycotics
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
  • C07C229/46—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
  • C07C229/48—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups and carboxyl groups bound to carbon atoms of the same non-condensed ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
  • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Definitions

• dipeptides from ⁇ -amino acids and / or their derivatives and cyclopentane- ⁇ -amino acids and / or derivatives thereof these unwanted side effects or not to a lesser extent and thus improved tolerance in warm-blooded animals is achieved.
• derivatives includes those compounds which are derived from the corresponding amino acids and have a comparable effect, in particular the corresponding salts.
• the present invention relates to dipeptides consisting of an ⁇ -amino acid or a derivative thereof and a cyclopentane- ⁇ -amino acid or a derivative thereof.
• R 6 is hydrogen
• Y represents the proportion of covalent binding of the ⁇ -amino acid and the cyclopentane- ⁇ -amino acid.
• the dipeptides of the invention may consist of substantially pure stereoisomers or mixtures of stereoisomers.
• ⁇ -amino acids, cyclopentane- ⁇ -amino acids and dipeptides described above can also be present in the form of their salts.
• salts with organic or inorganic bases or acids and internal salts may be mentioned here.
• Physiologically acceptable salts may also be metal or ammonium salts of the compounds of the invention which have a free carboxyl group. Particularly preferred are e.g. Sodium, potassium, magnesium or calcium salts, and ammonium salts derived from ammonia or organic amines such as ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine or phenethylamine.
• the dipeptides according to the invention may exist in stereoisomeric forms, for example either as image and mirror image (enantiomers), or the do not behave as image and mirror image (diastereomers), or exist as a mixture of diastereomers or as pure cis or trans isomers.
• the invention relates to both the antipodes, racemic forms, diastereomer mixtures and the pure isomers.
• the racemic forms can be separated as well as the diastereomers in a known manner in the stereoisomerically uniform components. The separation into the stereoisomerically uniform compounds takes place, for example, via a chromatographic resolution of diastereomeric esters and amides or on optically active phases. In addition, a crystallization of diastereomeric salts is possible.
• amino acid residues defined by the radical are in the L form.
• R 10 stands for an amino protecting group and R 11 is an activating protective group customary in peptide chemistry, preferably for the hydroxysuccinimide ester radical or R 10 and R 11 together for the grouping stand, first into the compounds of general formula (IV) in which R 1 , R 2 , R 3 , R 4 and R 10 have the meanings given above, in solvents and in the presence of a base überbowt, and finally the amino protecting group (R 10 ) splits off, optionally separating the stereoisomers, and in the case of esters (R 6 ⁇ H in formula (Ib)) the acids are reacted by conventional methods with the corresponding alcohols.
• the dipeptides are converted into the salts by customary methods.
• Amino-protecting groups (R 10 ) in the context of the invention are the usual amino-protecting groups used in peptide chemistry.
• benzyloxycarbonyl 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, Methoxycarbonyl, ethoxycarbonyl, tert -butoxycarbonyl, allyloxycarbonyl, vinyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, phthaloyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-trichloro-tert-butoxycarbonyl, menthyloxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9- methoxycarbonyl (Fmoc), formyl, acetyl, propionyl, pivaloyl
• Suitable activating carboxyl radicals are generally adducts with carbodiimides, for example N, N-diethyl, N, N-diisopropyl, N, N-dicyclohexylcarbodiimide, N- (3-dimethylaminoisopropyl) -N'-ethyl-carbodiimide- Hydrochloride, N-cyclohexyl-N- (2-morphlinoethyl) -carbodiimide-metho-p-toluenesulfonate, or carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3 sulfate or 2-tert-butyl-5-methyl-isoxazolium perchlorate, or acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquino
• alkali metal carbonates e.g. Sodium or potassium carbonate or bicarbonate
• organic bases such as trialkylamines, e.g. Triethylamine, ethyldiisopropylamine, N-ethylmorpholine, N-methylpiperidine or N-methylmorpholine
• Triethylamine e.g. Triethylamine, ethyldiisopropylamine, N-ethylmorpholine, N-methylpiperidine or N-methylmorpholine
• Preference is given to N-methylmorpholine.
• the auxiliaries and bases are used in an amount of 1.0 mol to 3.0 mol, preferably 1.0 mol to 1.2 mol, based on 1 mol of the compounds of general formula (III).
• the reactions are carried out in a temperature range from 0 ° C to 100 ° C, preferably at 0 ° C to 30 ° C and at atmospheric pressure.
• the reactions can be carried out both at atmospheric pressure and at elevated or reduced pressure (for example, 0.5 to 5 bar), preferably at atmospheric pressure.
• the cleavage of the amino protecting group is generally carried out in a conventional manner under acidic or basic conditions, or reductively by catalytic hydrogenation, for example with Pd / C in organic solvents such as ethers, e.g. Tetrahydrofuran or dioxane, or alcohols, e.g. Methanol, ethanol or isopropanol.
• organic solvents such as ethers, e.g. Tetrahydrofuran or dioxane, or alcohols, e.g. Methanol, ethanol or isopropanol.
• the hydrogenation is carried out at elevated pressure of from 2 bar to 8 bar, preferably from 3 to 5 bar.
• suitable bases such as piperidine, morpholine, dicyclohexylamine, p-dimethylaminopyridine, diisopropylethylamine or piperazine. Preference is given to piperidine.
• the auxiliaries and bases are used in an amount of 1.0 mol to 3.0 mol, preferably 1.0 mol to 1.2 mol, based on 1 mol of the compounds of general formula (IV).
• the reactions are carried out in a temperature range from 0 ° C to 100 ° C, preferably at 0 ° C to 30 ° C and at atmospheric pressure.
• the reactions can be carried out both at atmospheric pressure and at elevated or reduced pressure (for example, 0.5 to 5 bar), preferably at atmospheric pressure.
• the compounds of the general formula (III) are known in some cases or can be prepared by customary methods.
• the daily doses were 2 x 25 mg / kg and 2 x 50 mg / kg body weight (BW), the treatment duration was 5 days.
• the survival rates of the treated animals were daily up to the 10th day p.i. written down. At this time no animals survived in the untreated control animals.
• the animals show bleeding in the medial corner of the eye just one day after infection; In addition to the kidney, other organ systems such as the brain, heart, liver, spleen, retina and lungs are affected. Substance administration is performed twice daily for five days perorally in 1 ml glucose (5%) - agar (0.2%) - solution beginning on the day of infection.
• (+) - 1,2-cis-2- (S) -alanyl-amino-4-methylene-cyclopentane-1-carboxylic acid The title compound is prepared analogously to the procedure of Example 1 from Example II (5.7 g, 13.1 mmol). The product is purified by column chromatography on silica gel (dichloromethane / methanol, 1: 1) and crystallized from methanol / isopropanol / acetone. Yield: 0.7 g (25% of theory) M.p.

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• Health & Medical Sciences (AREA)
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• Organic Chemistry (AREA)
• Life Sciences & Earth Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Pharmacology & Pharmacy (AREA)
• Animal Behavior & Ethology (AREA)
• Epidemiology (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Gastroenterology & Hepatology (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Oncology (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Immunology (AREA)
• Communicable Diseases (AREA)
• Genetics & Genomics (AREA)
• Biophysics (AREA)
• Biochemistry (AREA)
• Molecular Biology (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Peptides Or Proteins (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Agricultural Chemicals And Associated Chemicals (AREA)
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• Pyrrole Compounds (AREA)

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